U.S. patent number 8,362,259 [Application Number 12/506,662] was granted by the patent office on 2013-01-29 for process for the preparation of esomeprazole magnesium in a stable form.
This patent grant is currently assigned to Lek Pharmaceuticals, D.D.. The grantee listed for this patent is Renata Toplak Casar. Invention is credited to Renata Toplak Casar.
United States Patent |
8,362,259 |
Toplak Casar |
January 29, 2013 |
Process for the preparation of esomeprazole magnesium in a stable
form
Abstract
There is provided a process for preparing purified esomeprazole
magnesium, comprising the steps of: providing esomeprazole
magnesium; contacting said esomeprazole magnesium with a
non-solvent comprising an aqueous component up to a maximum content
defined by water saturation in the non-solvent; and recovering
purified esomeprazole magnesium formed from the contacting step.
The process is particularly suitable to obtain esomeprazole
magnesium dihydrate, especially form A. The esomeprazole magnesium
obtained is remarkably pure, stable and is resistant to form
interchangeability.
Inventors: |
Toplak Casar; Renata
(Ljubljana, SI) |
Applicant: |
Name |
City |
State |
Country |
Type |
Toplak Casar; Renata |
Ljubljana |
N/A |
SI |
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Assignee: |
Lek Pharmaceuticals, D.D.
(Ljubljana, SI)
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Family
ID: |
39970890 |
Appl.
No.: |
12/506,662 |
Filed: |
July 21, 2009 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20100016370 A1 |
Jan 21, 2010 |
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Foreign Application Priority Data
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Jul 21, 2008 [EP] |
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08160826 |
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Current U.S.
Class: |
546/273.7 |
Current CPC
Class: |
C07D
401/12 (20130101); A61P 29/00 (20180101); A61P
1/04 (20180101) |
Current International
Class: |
C07D
401/12 (20060101) |
Field of
Search: |
;546/273.7 |
Foreign Patent Documents
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2166794 |
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Jan 1995 |
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CA |
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2254572 |
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Oct 1999 |
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CA |
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0 005 129 |
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Oct 1979 |
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EP |
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0 124 495 |
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Nov 1984 |
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EP |
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1 230 237 |
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Aug 2002 |
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EP |
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1 375 497 |
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Jan 2004 |
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EP |
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WO 94/27988 |
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Dec 1994 |
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WO |
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WO 95/01977 |
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Jan 1995 |
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WO |
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WO 97/41114 |
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Nov 1997 |
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WO |
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WO 98/54171 |
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Dec 1998 |
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WO |
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WO 01/36572 |
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May 2001 |
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WO |
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WO 01/87831 |
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Nov 2001 |
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WO |
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WO 2004/020436 |
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Mar 2004 |
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WO |
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WO 2004/037253 |
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May 2004 |
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WO |
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WO 2004/046134 |
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Jun 2004 |
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WO |
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WO 2004/076440 |
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Sep 2004 |
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WO |
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WO 2004/089935 |
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Oct 2004 |
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WO |
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WO 2006/003163 |
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Jan 2006 |
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WO |
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WO 2006/096709 |
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Sep 2006 |
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WO |
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WO 2007/031845 |
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Mar 2007 |
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WO |
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WO 2007/071753 |
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Jun 2007 |
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WO |
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WO 2007/140608 |
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Dec 2007 |
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WO |
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WO 2008/102145 |
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Aug 2008 |
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WO |
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Other References
Kirk-Othmer Encyclopedia of Chemical Technology, vol. 8, p. 95-147
(2002). cited by examiner.
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Primary Examiner: Morris; Patricia
Attorney, Agent or Firm: Arent Fox LLP
Claims
The invention claimed is:
1. A process for preparing purified esomeprazole magnesium
dihydrate form A, comprising the steps of: providing esomeprazole
magnesium; contacting said esomeprazole magnesium with a solvent or
mixture of solvents in which the esomeprazole magnesium has a
maximum solubility of 5 g/L, wherein said solvent or mixture of
solvents comprises an aqueous component provided in an amount up to
a maximum content defined by water saturation in the solvent or
mixture of solvents; and recovering purified esomeprazole magnesium
dihydrate form A formed from the contacting step, wherein the
esomeprazole magnesium dihydrate form A is characterized by having
an X-ray diffraction pattern with characteristic peaks (2.theta.)
that are exactly or within .+-.0.2 degrees 2.theta. of the
following values: 5.7, 13.4, 14.4, 18.8 and 21.2.
2. The process according to claim 1, wherein said provided
esomeprazole magnesium is in a first polymorphic form, which based
on said contacting step is converted into a second polymorphic form
comprising esomeprazole magnesium dihydrate form A, wherein said
first polymorphic form is not esomeprazole magnesium dihydrate form
A.
3. The process according to claim 2, wherein said first polymorphic
form of esomeprazole magnesium is defined by at least one form
selected from amorphous, hydrate, and mixed forms thereof, and
wherein said prepared, second polymorphic form of esomeprazole
magnesium is esomeprazole magnesium dihydrate form A.
4. The process according to claim 1, wherein said aqueous component
consists of water.
5. The process according to claim 1, wherein said provided
esomeprazole magnesium is a magnesium salt in amorphous or hydrate
form, optionally containing higher content of residual solvents up
to 5% by weight.
6. The process according to claim 5, wherein said provided
esomeprazole magnesium salt is in amorphous form, monohydrate form,
or dihydrate form.
7. The process according to claim 1, wherein said provided
esomeprazole magnesium was prepared from neutral esomeprazole by
reaction with magnesium source.
8. The process according to claim 1, wherein said provided
esomeprazole magnesium is provided in solid form.
9. The process according to claim 1, wherein the maximum solubility
of esomeprazole magnesium is 3 g/l.
10. The process according to claim 1, wherein said non-solvent is
selected from the group consisting of esters and ethers.
11. The process according to claim 1, wherein said non-solvent is
selected from the group consisting of methyl acetate, ethyl
acetate, isopropyl acetate, diethyl ether, diisopropyl ether and
methyl t-butyl ether.
12. The process according to claim 1, wherein said non-solvent is
ethyl acetate.
13. The process according to claim 1, wherein more than 20% of said
purified esomeprazole magnesium formed from the contacting step is
crystalline.
14. The process according to claim 1, wherein the esomeprazole
magnesium dihydrate form A is characterized by having an X-ray
diffraction pattern with additional characteristic peaks (2.theta.)
that are exactly or within .+-.0.2 degrees 2.theta. of the
following values: 15.1, 16.6, 17.0, 19.5, 20.5, 21.9, 28.0, 28.4,
and 29.3.
Description
CROSS-REFERENCE TO RELATED APPLICATION
This application claims priority to European Patent Application No.
08160826.7, filed on Jul. 21, 2008, the contents of which are
incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
The present invention relates in general to the field of
pharmaceutical compositions and in particular to the preparation of
a salt of esomeprazole, in particular magnesium salt of
esomeprazole, which may be used in a pharmaceutical
composition.
BACKGROUND OF THE INVENTION
The compound known under the generic name omeprazole is disclosed
in EP 0 005 129.
Omeprazole is useful for inhibiting gastric acid secretion and has
gastric mucosa protective activity in mammals and man. Omeprazole
may be used for prevention and treatment of gastric acid related
disorders and gastrointestinal inflammatory diseases in mammals and
man, including for example gastritis, gastric ulcer and duodenal
ulcer.
Certain salts of omeprazole are disclosed in EP 0 124 495. Canadian
patent 2166794 disclosed a form of magnesium omeprazole dihydrate,
which has a higher degree of crystallinity. This form has a
methanol content of less than 0.1%.
Canadian patent application No. 2254572 discloses a process for the
production of magnesium omeprazole crystalline dihydrate.
The S-enantiomer of omeprazole commonly referred as esomeprazole is
said to have improved pharmacokinetical properties which give an
improved therapeutic profile such as lower degree of
inter-individual variation (WO 94/27988). Esomeprazole magnesium,
the generic name for magnesium
bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl-
]-1H-benzimidazole), is a well-known gastric proton-pump inhibitor
and has been commercially available from AstraZeneca under the
brand name NEXIUM since 2001.
WO 94/27988 describes a solid form of esomeprazole magnesium, WO
95/01977 describes solid omeprazole magnesium with a degree of
crystallinity over 70%.
WO 98/54171 describes a magnesium salt of esomeprazole trihydrate
characterized by being highly crystalline and stable. It discloses
also polymorphic forms (A and B) of esomeprazole magnesium salt
dihydrate and processes for their preparation using esomeprazole
potassium salt as an intermediate.
WO 04/046134 describes a crystalline esomeprazole magnesium salt
trihydrate form II wherein the term trihydrate is used to define a
crystalline material in which water molecules are bound in the
crystalline lattice. WO 04/089935 provides new polymorphic forms of
crystalline esomeprazole magnesium trihydrate, hemihydrate and
monohydrate. WO 07/031845 discloses novel polymorphs of
esomeprazole magnesium trihydrate (G1 and G2) and processes for
their preparation. In addition, a new process for preparing
amorphous esomeprazole magnesium is presented. Therefore the
preparation of esomeprazole magnesium trihydrate may suffer on
repeatability because many forms are possible which could be
interchangeable.
Numerous patent applications WO 01/87831, WO 04/037253, WO
04/020436, WO 06/096709, and WO 07/0710753 describe amorphous
esomeprazole magnesium with various amounts of water and residual
solvents. Again no clear procedure for a unique form can be
concluded.
It is generally known that safety and also stability of an active
pharmaceutical ingredient depends among other factors strongly upon
residual solvents content.
To diminish the effect of residual solvents they should be all
removed to the highest possible extend from an active
substance.
EP 1 230 237 describes a procedure of removing residual solvents in
omeprazole magnesium and EP 1 375 497 a procedure of removing
residual solvents in esomeprazole magnesium by flash evaporation
but the products have unrepeatable low crystallinity between
amorphous and a degree of crystallinity around 25% and still
contain various amounts of residual solvents.
The object of the present invention thus was to provide a process
for preparing esomeprazole magnesium in a purified and stable form
and in repeatable manner even if scaled up, and to correspondingly
provide such a purified, stable and reproducible form of
esomeprazole magnesium.
SUMMARY OF THE INVENTION
The present invention provides the following items including main
aspects and preferred embodiments, which respectively alone and in
combination particularly contribute to solving the above object and
eventually provide additional advantages: (1) A process for
preparing purified esomeprazole magnesium, comprising the steps of:
providing esomeprazole magnesium; contacting said esomeprazole
magnesium with a non-solvent comprising an aqueous component up to
a maximum content defined by water saturation in the non-solvent;
and recovering purified esomeprazole magnesium formed from the
contacting step.
As used herein, the term "non-solvent" is meant as a solvent or
mixture of solvents in which the provided esomeprazole magnesium is
insoluble or poorly soluble. A suitable non-solvent can be defined
by showing a maximum solubility of 5 g/L, preferably maximum
solubility of 3 g/L.
The non-solvent is made wet ("wet non-solvent") by adding an
aqueous component. As used herein, the term "aqueous component"
means water, or a mixture of water with a water-soluble organic
solvent. The aqueous component is preferably water alone. Suitable
water-soluble organic solvents which can be included into the
aqueous component are alcanols, e.g. methanol or ethanol; ketones,
e.g. acetone; dipolar aprotic solvents, e.g. DMF or DMSO;
respectively alone or in combination, without being limited
thereto. Addition of a water-soluble organic solvent to the aqueous
component is possible in order to slightly increase solubility of
water in some non-solvents such as ethers. But the amount of the
added water-soluble organic solvent should be small, preferably
very small in order to prevent interchangeability or conversion to
some other polymorphic form. Amount of the a water-soluble organic
solvent in the mixture therefore preferably does not exceed 5
wt.-%, more preferably does not exceed 2.5 wt.-%.
Amount of the aqueous component, preferably water alone, in the
non-solvent is preferably at least 1 wt.-% up to water saturation,
preferably up to 5 wt.-%.
It has been surprisingly found that during a contact with a wet
non-solvent which is obtained by including a small amount of an
aqueous component and in particular water alone in an amount of
maximally water saturation, a product is obtainable which has a
remarkable chemical and physical stability and thus, also due to
very low content of residual solvent, is valuable as an active
pharmaceutical ingredient. It is feasible to repeatedly yield
stable and pure esomeprazole magnesium in crystal form. Although
not bound to any theory, it is believed that during the wet
non-solvent treatment, esomeprazole magnesium undergoes a
beneficial and stabilising structural rearrangement, while at the
same time allowing to reduce solvent components of the starting
esomeprazole magnesium. The contacting step is typically carried
out for a time sufficient to obtain the desired purification effect
and preferably the stabilising effect. A treatment period of 10 min
to 48 hours may be suitable, a period of 0.5 to 24 hours,
especially of 1 to 8 hours being preferred. (2) The process
according to item (1), wherein said non-solvent is selected from
the group consisting of esters and ethers. (3) The process
according to item (1) or (2), wherein said non-solvent is selected
from the group consisting of methyl acetate, ethyl acetate,
isopropyl acetate, diethyl ether, diisopropyl ether and methyl
t-butyl ether. (4) The process according to any one of items (1) to
(3), wherein said non-solvent is ethyl acetate. (5) The process
according to any one of items (1) to (4), wherein said provided
esomeprazole magnesium is in a first polymorphic form, which based
on said contacting step is converted into a second polymorphic form
of esomeprazole magnesium different from said first polymorphic
form.
According to this preferred embodiment, said first, starting form
of esomeprazole can be consistently and thus repeatedly converted
into a second form of esomeprazole magnesium. As desired, the
duration of the contacting step may be limited to obtain a
controlled mixture of both first and second forms esomeprazole
magnesium. (6) The process according to any of items (1) to (5),
wherein said first polymorphic form of esomeprazole magnesium is
defined by at least one form selected from amorphous or any
crystalline form or intermediate forms, including especially
anhydrous, hydrate, solvate and mixed forms thereof, and wherein
said prepared, second polymorphic form of esomeprazole magnesium is
esomeprazole magnesium dihydrate. As hydrate, hemihydrate,
monohydrate, dihydrate, sesquihydrate, trihydrate are particularly
mentioned, and as other solvates, alcoholate such as methanolate
and ethanolate; ketonate such as acetonate; esterate such as ethyl
acetylate; etherate such as diethyletherate; hydrocarbon solvate
such as toluene solvate or alkylchloride such as dichloromethane
solvate, are particularly mentioned, without being limited to
thereto. Remarkably, the process according to the present invention
is specifically tailored to the repeatable and consistent
production of the dihydrate form of esomeprazole magnesium,
especially in its crystalline form and with high chromatographic
purity. In spite a variety of optionally selectable first
polymorphic forms, surprisingly the dihydrate form of esomeprazole
magnesium can be obtained with high stability and polymorphic
purity. (7) It is thus a useful independent aspect of the present
invention to provide a process for preparing esomeprazole magnesium
dihydrate, comprising the steps of: providing esomeprazole
magnesium; contacting said esomeprazole magnesium with a
non-solvent comprising an aqueous component up to a maximum content
defined by water saturation in the non-solvent; and recovering
esomeprazole magnesium dihydrate formed.
Concerning meanings of expressions, features and preferred
embodiments, reference is made to the description above. (8) The
process according to item (7), wherein said provided esomeprazole
magnesium is in amorphous form or in dihydrate form B which, upon
said contacting step, is respectively converted into dihydrate form
A of esomeprazole magnesium.
A conversion of amorphous form or dihydrate form B into dihydrate
form A is a remarkably repeatable process and makes the provision
of extremely pure and stable form of esomeprazole magnesium
feasible. The extend of conversion is made as far as desired;
preferably it is a major conversion of at least 50%, more
preferably at least 60%. (9) The process according to any one of
items (1) to (8), wherein more than 20% of said purified
esomeprazole magnesium formed from the contacting step is
crystalline. (10) The process according to any one of the preceding
items, wherein said aqueous component consists of water.
Using water alone as a component of the wet non-solvent makes the
treatment particularly effective. (11) The process according to any
one of the preceding items, wherein said provided esomeprazole
magnesium was prepared from neutral esomeprazole by reaction with
magnesium source.
By this measure a reliable, robust and efficient conversion of
neutral form into magnesium salt form of esomeprazole is ensured.
This preferred embodiment obviates the need of alkaline salt of
esomeprazole such as potassium or sodium salt as intermediary
substance. It further ensures high yield and chemical, optical,
alkali metal and polymorphic purity of the product. (12) The
process according to any one of items (1) to (11), wherein said
provided esomeprazole magnesium is a magnesium salt in amorphous or
hydrate or solvate form, optionally containing higher content of
residual solvents up to 5% by weight. (13) The process according to
item (12), wherein said esomeprazole magnesium salt is in
amorphous, monohydrate form, dihydrate form B or acetone solvate
form. (14) The process according to any one of items (1) to (13),
wherein said provided esomeprazole magnesium is provided in solid
form. (15) Crystal form of esomeprazole magnesium with a
chromatographic (HPLC) purity of at least 99.0%, obtained by wet
non-solvent treatment of esomeprazole magnesium. Any starting form
of esomeprazole magnesium can be subjected to the treatment, for
example those mentioned as the first polymorphic form in item (6)
above. Treatment can be done by contacting such starting form of
esomeprazole magnesium with a non-solvent comprising aqueous
component, in particular water, up to a maximum content defined by
water saturation. Concerning the term "non-solvent", reference is
made to the definition under item (1) above.
The process of the present invention not only surely and repeatedly
results in high chromatographic purity, but inherently achieves
also stable maintenance of magnesium form of esomeprazole without
impurity formation even under longterm or stress storage
conditions. (16) Crystal form of esomeprazole magnesium according
to item (15), wherein the esomeprazole magnesium subjected to wet
non-solvent treatment is provided in solid form. (17) Crystal form
of esomeprazole magnesium according to item (15) or (16), wherein
the esomeprazole magnesium subjected to wet non-solvent treatment
is provided in amorphous, monohydrate form, dihydrate form B, or
acetone solvate form. (18) Crystal form of esomeprazole magnesium
according to any one of items (15) to (17), wherein the non-solvent
used for wet non-solvent treatment is a solvent or a mixture of
solvents, in which the maximum solubility of esomeprazole magnesium
is 5 g/l. (19) Crystal form of esomeprazole magnesium according to
any one of items (15) to (18), wherein the non-solvent used for wet
non-solvent treatment is a solvent or a mixture of solvents, in
which the maximum solubility of esomeprazole magnesium is 3 g/l.
(20) Crystal form of esomeprazole magnesium according to any one of
items (15) to (19), wherein the non-solvent used for wet
non-solvent treatment was selected from the group consisting of
esters and ethers. (21) Crystal form of esomeprazole magnesium
according to any one of items (15) to (20), wherein the non-solvent
used for wet non-solvent treatment was selected from the group
consisting of methyl acetate, ethyl acetate, isopropyl acetate,
diethyl ether, diisopropyl ether and methyl t-butyl ether. (22)
Crystal form of esomeprazole magnesium according to any one of
items (15) to (21), wherein the non-solvent used for wet
non-solvent treatment was ethyl acetate. (23) Crystal form of
esomeprazole magnesium with a chromatographic (HPLC) purity of at
least 99.7%, preferably at least 99.8%, more preferably at least
99.9% and even at least 99.95% is achievable. Such high purity
levels become possible when starting the wet non-solvent treatment
with esomeprazole magnesium showing already a chromatographic
(HPLC) purity of at least 99.5%. (24) Crystal form of esomeprazole
magnesium according to any one of items (15) to (23), wherein the
crystal form of esomeprazole magnesium is obtained as the dihydrate
form, in particular Form A. Subjecting esomeprazole magnesium to
treatment by wet non-solvent for a time sufficient is particularly
suited for repeatedly yielding the dihydrate form stably and at
extreme high purity. (25) Crystal form of esomeprazole magnesium
dihydrate with residual content of total organic solvent of 1 wt.-%
or below.
Total content of residual organic solvent in crystal form of
esomeprazole magnesium dihydrate can be drastically reduced
according to the present invention to a range of below about 1
wt.-%, preferably below about 0.5 wt.-%, more preferably below
about 0.1 wt.-%, and even below about 500 ppm. When the
esomeprazole magnesium salt is--as usual--prepared by procedures
conducted in organic solvents, the substantial organic solvent
reduction to levels acceptable for pharmaceutical applications,
preferably to lie within a range of above 0.00 to 0.10 wt.-%, is a
particularly beneficial feature. Conventional solvent removal
methods, notably simple drying or evaporation process, are
unsuitable to achieve such very low levels. Furthermore, these
methods are subject to risks of polymorph conversion or
esomeprazole decomposition; especially trying to achieve further
reduction by involving harsh conditions for solvent removal tends
to decompose esomeprazole magnesium dihydrate crystal form. A
suitable method of determining residual content of solvent is by
chromatography, typically gas chromatography (GC). Residual water
content can be tolerated. (26) Crystal form of esomeprazole
magnesium according to any one of items (15) to (25), wherein the
sum of omeprazole related substances other than esomeprazole,
including all impurities detectable by HPLC while disregarding
solvent impurities, is within a range of 0.05% or below, and is
preferably maintained within said range under stress stability
testing conditions measured by 60.degree. C./7 days/closed
packaging-treatment or 40.degree. C./75% RH/14 days/open
vial-treatment.
When the pure and stable form of esomeprazole magnesium, preferably
dihydrate form and especially Form A described above, is prepared
according to the present invention, unique chemical and physical
stability features are obtained as indicated, combined for example
with a chromatographic (HPLC) purity of esomeprazole magnesium
dihydrate significantly higher than 99.7%, e.g. at least 99.8%. On
the other hand, other esomeprazole forms which did not undergo wet
non-solvent treatment according to the present invention do not
repeatedly meet the purity characteristics, and moreover produce
omeprazole related substance impurities at a sum of more than 0.05%
under the afore-defined stress stability testing conditions.
%-indications correspond to % under the curve of HPLC run. (27)
Crystal form of esomeprazole magnesium according to one of items
(15) to (26) in dihydrate form, preferably in "Form A" being
characterized by at least five significant peaks at 2.theta. values
of 5.7, 13.4, 14.4, 18.8 and 21.2 in XRD diffractogram,
respectively exactly or .+-.0.2 degrees 2.theta. at the indicated
2.theta. values, preferably being characterized by peaks at
2.theta. values of 5.7, 13.4, 14.4, 15.1, 16.6, 17.0, 18.8, 19.5,
20.5, 21.2, 21.9, 28.0, 28.4, 29.3 in XRD diffractogram,
respectively exactly or .+-.0.2 degrees 2.theta. at the indicated
2.theta. values, preferably as shown in FIGS. 1 and 2. (28) The
crystal form of esomeprazole magnesium dihydrate according to any
one of items (15) to (27), with a polymorphic purity being defined
by being essentially free of each of other crystalline forms
including anhydrous, hydrate and other solvate polymorphic forms,
in particular being essentially free of anhydrous, monohydrate,
hemihydrate, sesquihydrate, trihydrate, alcoholate (methanolate,
ethanolate) and other solvate (generally defined by organic solvent
molecule used during isolation of the dihydrate form, in particular
hydrocarbon such as toluene, alkylchlorides, ether and ester
solvates) polymorphic forms. As used herein, the term "essentially
free" is typically referred to a content of less than 5 wt.-%,
preferably less than 2 wt.-% and more preferably less than 1 wt.-%.
Residual amorphous form may be tolerated at a higher content such
as up to 50 wt.-%, possibly up to 40 wt.-%, corresponding to a
degree of crystallinity, calculated according to the method
described in WO97/41114, of at least around 50%, preferably at
least around 60%.
Since the wet non-solvent treatment of esomeprazole magnesium can
be tailored specifically towards the dihydrate form, conversion
from the starting form from which treatment was started can be made
effective in a manner to substantially reduce the starting form,
used either alone or in admixture. (29) A pharmaceutical
preparation comprising the crystal form of esomeprazole magnesium
according to any one of items (15) to (28) and a pharmaceutically
acceptable excipient.
Owing to the stable and highly pure esomeprazole magnesium, in
particular the dihydrate form and especially Form A, repeatedly
obtained according to the present invention, it is particularly
suited for medical use in a pharmaceutical composition containing
usual excipients. (30) The form of esomeprazole magnesium dihydrate
according to any one of items (15) to (28), and the pharmaceutical
preparation according to item (29) for use in treatment of a
gastrointestinal inflammatory disease or condition. The
esomeprazole magnesium forms and the pharmaceutical preparation
according to the present invention is particularly suitable as
anti-ulcer agent.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows conversion of amorphous esomeprazole magnesium to
esomeprazole dihydrate form A according to Example 1 detected by
XRPD
FIG. 2 shows conversion of esomeprazole magnesium dihydrate form B
to dihydrate form A according to Example 4 detected by XRPD
FIG. 3 shows conversion of amorphous esomeprazole magnesium to
esomeprazole dihydrate form A according to Example 1 detected by
DSC
FIG. 4 shows conversion of esomeprazole magnesium dihydrate form B
to dihydrate form A according to Example 4 detected by DSC.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is now described in more detail by referring
to further preferred and further advantageous embodiments and
examples, which are however presented for illustrative purposes
only and shall not be understood as limiting the scope of the
present invention.
According to the present invention, a simple industrially
applicable process is provided for preparation of chemically and
physically stable crystalline esomeprazole magnesium salt with low
content of residual solvents (less than 1% by weight, less than
0.5% by weight, less than 0.2% by weight). The most stable
crystalline esomeprazole magnesium with low content of residual
solvents according to the invention is dihydrate form A according
to nomenclature of WO 98/54171. Surprisingly little is known how to
prepare dihydrates of esomeprazole magnesium, mentioned in WO
98/54171, in form free of residual solvents by a process which can
be scaled to the industrial level. Stable dihydrates of appropriate
quality which could be prepared in a repeatable manner provides
useful final form of esomeprazole magnesium for pharmaceutical
application.
According to literature data (EP 1230237, EP 1375497) residual
organic solvents are hardly removed from omeprazole or esomeprazole
magnesium salts which are prepared by procedures conducted in
organic solvents. Especially, when the prepared product is in
amorphous form or in a form with low degree of crystallinity
residual solvents are entrapped in solid particles and cannot be
easily removed by evaporation or drying. Furthermore, due to
molecule(s) of solvent incorporated in a crystal lattice a higher
content of residual solvents that can not be reduced by simple
drying or evaporation, is characteristic also for products in
solvated form. By the term "simple drying or evaporation process"
we understand processes conducted by conventional methods at
conditions (temperature, reduced pressure) that do not effect
quality of the obtained product regarding purity or physical
properties.
Esomeprazole can be prepared by enantioselective chemical
reaction--notably by oxidation of sulphide-, by separation of
S-enantiomer from racemate (enantiopurification), via
diastereoisomeric derivatisation of omeprazole or by any other
suitable process. Preferred is separation by chiral chromatography
of racemic omeprazole, for example as described in WO
07/071753.
When the process is started with neutral esomeprazole, it can be
transferred into magnesium salt directly by reaction with magnesium
source, or via other salt forms followed by conversion into
magnesium salt by adding magnesium salt. The magnesium source may
be selected from the group consisting of magnesium sulphate,
magnesium chloride, magnesium 2-ethyl-hexanoate, magnesium citrate,
magnesium stearate, magnesium ascorbate, magnesium acetate,
magnesium ethanolate, magnesium methanolate, and mixtures thereof.
Magnesium methanolate is preferred. Preferably, the starting
substance is obtained by reacting esomeprazole with magnesium
methanolate as a magnesium source in methanol solution and further
precipitating the substance by addition of non-solvent (e.g. ether,
acetate) or addition of crystallizing media (e.g. mixture of
acetone and water).
It is prepared from crude esomeprazole magnesium salt in amorphous
or hydrate or solvate, which can be obtained by any known process
for preparation of amorphous or hydrate or solvate form of
esomeprazole magnesium.
The process according to the present invention does not require any
alkaline salt of esomeprazole as intermediary substance and it
ensures high yield and purity (chemical, optical, alkali metal,
polymorphic) of the product. For example, preparation of
esomeprazole magnesium dihydrate form A and form B previously
described in WO 98/54171 involves a two-step procedure using
esomeprazole potassium salt as an intermediate which is further
converted with MgSO.sub.4x7H.sub.2O to magnesium salt of
esomeprazole and crystallized from a mixture of methanol, acetone
and water. The procedures for preparation of both polymorphic forms
of esomeprazole magnesium dihydrate according to WO 98/54171 are
very similar and do not ensure reproducible formation of a product
of polymorphic purity.
Surprisingly, it was discovered that esomeprazole magnesium salt in
amorphous or hydrate or solvate (monohydrate, hemihydrate,
dihydrate form B, acetone solvate) form, optionally containing
higher content of residual solvents (up to 5% by weight), can be
transformed into chemically and physically stable and pure
esomeprazole magnesium form, in particular to dihydrate form, and
especially to form A having low content of residual solvents by a
simple process. The process can preferably yield improved product
of dihydrate form A. Transformation occurs by simple digestion
process of the starting material in a non-solvent containing small
amount of water (wet non-solvent). As digestion we denote a process
of suspending a substance in a solvent or a mixture of solvents in
which it is insoluble or poorly soluble (commonly briefly denoted
as "non-solvent") and stirring the suspension for a certain period
of time, preferably 0.5-24 hours, most preferably 1-8 hours. A
non-solvent is preferably selected from a group of esters,
preferably acetates (methyl acetate, ethyl acetate, isopropyl
acetate) or from a group of ethers (diethyl ether, diisopropyl
ether, methyl t-butyl ether), most preferably ethyl acetate is
used. The non-solvent contains a small amount of water, preferably
from 1% to saturation. Most preferably ethyl acetate with up to 5%
by weight of water is applied in the process. During the process of
digesting the starting material esomeprazole magnesium salt in
amorphous or hydrate or solvate form is converted into more
physically stable crystal structure of esomeprazole magnesium,
especially by targeting to esomeprazole magnesium dihydrate and in
particular its form A. After recovery and drying of the obtained
precipitate, a product with low content of residual solvents is
produced by simple drying or evaporation process. No drying in an
atmosphere with increased relative humidity or any special
treatment is needed to try to eliminate residual solvents. Thus,
wet solvent treatment allows the isolated compound (especially
dihydrate form A) to treat further to thereby easily and gently
remove residual solvents further by simple drying or evaporation
process without any risk of changes of polymorphic or chemical
characteristics.
On the other hand polymorphic forms conventionally prepared in
organic solvents and thus not being in a proper condition as
according to the present invention, which are then defined by other
forms, content of the residual organic solvents can be lowered only
by drying the product under harsh conditions or by applying special
techniques and this is likely to cause changes in polymorphic or
chemical purity.
According to the particularly preferred embodiment, conversion of
esomeprazole magnesium of less defined forms, low crystalline
forms, mixture of forms, amorphous or of less thermodynamically
stable forms such as esomeprazole magnesium dihydrate form B into
esomeprazole magnesium dihydrate form A by the disclosed procedure
(Scheme 1) is a highly repeatable process. The conversion was
monitored by XRPD and DSC analysis. Comparison of XRPD
diffractograms and DCS thermograms of starting materials and
products is presented in FIGS. 1-4.
##STR00001##
Further, besides thermodynamic stability esomeprazole magnesium
dihydrate form A, prepared according to the preferred embodiment of
the invention, exhibits greater chemical stability in comparison of
some other forms. Illustratively, it was tested under regular
pharmaceutical tests such as stress condition test (Table 1) and
was compared with chemical stability of the starting amorphous
esomeprazole magnesium or esomeprazole Mg dihydrate form B (Table
2).
TABLE-US-00001 TABLE 1 The results of 14 days stress stability
testing of esomeprazole Mg dihydrate form A Esomeprazole magnesium
dihydrate form A Storage conditions Initial analysis 60.degree. C.
40.degree. C./75 RH, open dish Time of testing 7 days 14 days
Packaging vial open vial HPLC - Related substances and degradation
products: Sum .ltoreq.0.05 .ltoreq.0.05 Chromatographic 99.85 99.82
99.85 purity
TABLE-US-00002 TABLE 2 The results of 14 days stress stability
testing of reference esomeprazole Mg samples (amorphous and
dihydrate form B). Defined impurities represent pharmacopoeial ones
(EuPharma) Amorphous esomeprazole Esomeprazole magnesium magnesium
dihydrate form B Storage conditions Initial 60.degree. C.
40.degree. C./75 RH, Initial 60.degree. C. 40.degree. C./75 RH,
analysis open dish analysis open dish Time of testing 7 days 14
days 7 days 14 days Packaging vial open vial vial open vial HPLC -
Related substances and degradation products (RRt): 0.10 0.04 0.11
0.12 0.09 0.16 0.06 0.18 0.07 0.20 0.06 0.04 OMP-benzimidazole 0.06
0.04 (Ph. Eur. Imp. A) OMP-N-oxide 0.03 (Ph. Eur. Imp. E)
OMP-N-sufone 0.03 (Ph. Eur. Imp. D) 1.45 0.04 0.15 0.06 1.59 0.06
1.61 0.06 2.20 0.07 0.09 2.25 0.09 Omeprazole-N-methyl 0.07 SUM
0.10 0.79 0.43 <0.05 0.07 0.14
Comparing the results of stress stability testing of all three
forms of esomeprazole magnesium it can be concluded that
esomeprazole magnesium in a form of dihydrate form A obtained
according to the present invention represents chemically the most
stable form.
In addition, also physical stability of esomeprazole magnesium
dihydrate form A obtained according to the present invention was
tested. The results of the testing prove that the polymorphic form
A is stable under the described stress conditions (14 days
40.degree. C./75% relative humidity, 7 days 60.degree. C.).
The products were analyzed by following methods:
X-Ray powder diffraction method:
Conditions for obtaining powder X-ray diffraction (XRPD) patterns:
The powder X-ray diffraction patterns were obtained by methods
known in the art using Philips X'Pert PRO diffractometer with
X'Celerator detector using CuK.alpha. radiation (tube operating at
45 kV and 40 mA) in the Bragg-Brentano (reflection) geometry. Data
were recorded from 2 to 40.degree.2.theta. in steps of
0.033.degree.2.theta. and the measurement time of 50 seconds per
step. Variable divergence and antiscatter slits were used to
maintain 12 mm of sample length irradiated.
Differential Scanning Calorimetry:
Conditions for obtaining DSC thermograms: Thermograms were obtained
with Mettler Toledo DSC822e differential scanning calorimeter. The
sample (4-6 mg) was placed in an unsealed aluminium pan with a hole
and heated at 5.degree. C./min in the temperature range from
30.degree. C. to 200.degree. C.
IR Spectroscopy Method:
Conditions for obtaining infrared spectra: Fourier transform
infrared (FTIR) spectra were recorded with a Nicolet Nexus
spectrometer. Spectra over a range of 4000 to 400 cm-1 with a
resolution of 2 cm.sup.-1 (16 scans) were recorded on KBr
tablets.
The present invention is illustrated but in no way limited by the
Examples 1-4. Examples 1, 2 show preparation of esomeprazole
magnesium dihydrate form A from amorphous esomeprazole magnesium.
Example 3, 4 represents preparation of esomeprazole magnesium
dihydrate form A from esomeprazole magnesium dihydrate form B.
EXAMPLES
Preparation of Starting Materials
Amorphous esomeprazole magnesium was prepared according to the
examples described in the patent application WO 07/071753 or by any
other process described in the patent or scientific literature.
Esomeprazole magnesium dihydrate form B was prepared by any process
described in patents (e.g. WO 98/54171) or scientific literature,
preferably according to the following procedure:
A stoichiometric amount of 7.6 wt.-% methanolic solution of
magnesium methanolate (18.1 mL) was added to the solution of 9.0 g
of esomeprazole (99.28% e.e.) in 100 mL of methanol. The obtained
reaction mixture was stirred at room temperature for 1 hour
allowing to form esomeprazole magnesium salt in the meantime. After
addition of 0.4 mL of water the reaction mixture was further
stirred for 30 min. The formed inorganic solid salts were separated
from the liquid by filtration through a layer of diatomite filter
medium (Celite.RTM.). The volume of filtrate was then reduced by
evaporation of methanol forming an esomeprazole magnesium solution
with concentration 40-45 wt.-%. A mixture of 51 mL of acetone and
2.9 mL of water was added to the concentrate. The mixture was
seeded with a 0.05 g of esomeprazole magnesium dihydrate form B.
After a few minutes a precipitate was formed and the suspension was
stirred for 4 hours. The product was filtered off, washed twice
with 10 mL of a mixture of acetone and methanol (4/1(V/V)). The wet
filter cake was dried for 20 hours at reduced pressure (200 mbar).
8.00 g of esomeprazole magnesium dihydrate form B was obtained
(99.84% e.e. determined by chiral HPLC, 100% purity determined by
HPLC, 6.1% of water content determined by Karl-Fisher, 1.98% of
residual solvents content (methanol, acetone) as determined by
GC).
Example 1
200 mL of ethyl acetate saturated with water was added to 18 g of
amorphous esomeprazole magnesium (99.88% purity determined by HPLC,
4.8% of water content determined by Karl-Fisher, 3.5% of Mg
determined by complexometric titration, assay of
C.sub.34H.sub.36N.sub.6O.sub.6S.sub.2Mg 99.42% determined by HPLC,
content of residual solvents as determined by GC: 0.25% of
methanol, 1.14% of methyl t-butyl ether, XRPD diffractogram of the
starting material is presented in the FIG. 1, DSC thermogram in the
FIG. 3). The suspension was stirred for 2 hours at room
temperature. Then the digested product was filtered off and washed
with 10 mL of ethyl acetate. The wet filter cake was dried for 48
hours at 40.degree. C. in vacuum. 16.31 g of esomeprazole magnesium
dihydrate form A was obtained (99.85% purity determined by HPLC,
5.38% of water content determined by Karl-Fisher, 3.7% of Mg
determined by complexometric titration, content of residual
solvents as determined by GC: 220 ppm EtOAc, XRPD diffractogram of
the product is presented in the FIG. 1, DSC thermogram in the FIG.
3).
Example 2
4.5 L of ethyl acetate saturated with water at 20.degree. C. was
added to 200 g of amorphous esomeprazole magnesium (99.54% purity
determined by HPLC, 6.82% of water content determined by
Karl-Fisher, 0.22% of residual methanol content as determined by
GC). The suspension was stirred for 2 hours at 20.degree. C. Then
the digested product was filtered off and washed with 500 mL of
ethyl acetate. The wet filter cake was dried for 48 hours at
40.degree. C. in vacuum. 186.83 g of esomeprazole magnesium
dihydrate form A was obtained (99.79% purity determined by HPLC,
6.41% of water content determined by Karl-Fisher, 3.6% of Mg
determined by complexometric titration, 0.07% of residual solvent
content as determined by GC).
Example 3
50 mL of ethyl acetate saturated with water was added to 5 g of
crystalline esomeprazole magnesium dihydrate form B with higher
content of residual solvents (6.1% of water content determined by
Karl-Fisher, 1.98% of residual solvents content (methanol, acetone)
as determined by GC). The suspension was stirred for 2 hours at
room temperature. Then the digested product was filtered off and
washed twice with 10 mL of ethyl acetate. The wet filter cake was
dried for 72 hours at 35.degree. C. in vacuum giving 4.6 g of
esomeprazole magnesium dihydrate form A (residual solvents content:
761 ppm of ethyl acetate as determined by GC).
Example 4
200 mL of ethyl acetate saturated with water was added to 20 g of
esomeprazole magnesium dihydrate form B (3.4% of Mg determined by
complexometric titration, 5.1% of water content determined by
Karl-Fisher, XRPD diffractogram FIG. 2, DSC thermogram FIG. 4). The
suspension was stirred for 2 hours at room temperature. Then the
digested product was filtered off and washed twice with 20 mL of
ethyl acetate. The wet filter cake was dried for 48 hours at
35.degree. C. in vacuum. 18.11 g of esomeprazole magnesium
dihydrate form A was obtained (XRPD diffractogram of the product is
presented in the FIG. 2, DSC thermogram in FIG. 4).
Comparative Example 1
Esomeprazole and Mg methanolate were reacted in methanol according
to the prior art process described in the Example 6 of EP 124495.
The prepared esomeprazole magnesium was further subjected to
evaporation and drying to give a product with residual methanol
content of approximately 7%.
Comparative Example 2
Further removing of residual solvents was studied on amorphous
esomeprazole magnesium by drying. Substantial removal of residual
solvents were achieved only at high temperatures and were
accompanied by chemical decomposition.
* * * * *